COELIAC DISEASE

Regulation of the T helper cell type 1 transcription factor T-bet in coeliac disease mucosa

I Monteleone^1,*, G Monteleone^1,*, G Del Vecchio Blanco¹, P Vavassori¹, S Cucchiara², T T MacDonald³, F Pallone¹

¹ Dipartimento di Medicina Interna e Centro di Eccellenza per lo studio delle malattie complesse e multifattoriali, Università Tor Vergata, Rome, Italy
² Pediatric Unit, University "La Sapienza", Rome, Italy
³ Division of Infection, Inflammation, and Repair, University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK

Correspondence to:
Correspondence to:
Dr G Monteleone
Dipartimento di Medicina Interna, Università Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy; Gi.Monteleone{at}Med.uniroma2.it

Background: In coeliac disease (CD) mucosa, the histological lesion is associated with marked infiltration of T helper cell type 1 (Th1) cells. However, the molecular mechanisms which regulate Th1 cell differentiation in CD mucosa are unknown.

Aims: To analyse expression of transcription factors which control the Th1 cell commitment in CD.

Patients: Duodenal mucosal samples were taken from untreated CD patients and normal controls.

Methods: Interferon (IFN-) and interleukin (IL)-4 RNA expression was examined in T lamina propria lymphocytes by quantitative reverse transcription-polymerase chain reaction. T-bet and STAT-4, two Th1 promoting transcription factors, and STAT-6 and GATA-3, transcription factors which govern T helper cell type 2 (Th2) cell polarisation, were examined in duodenal biopsies by western blotting. The effect of gliadin and IFN- on expression of T-bet was examined in an ex vivo culture of biopsies taken from normal and treated CD patients.

Results: As expected, IFN- but not IL-4 RNA transcripts were increased in the mucosa of CD patients in comparison with controls. CD mucosal samples consistently exhibited higher levels of T-bet than controls. However, no difference in active STAT-4 expression was seen between CD patients and controls, suggesting that Th1 polarisation was not induced by local IL-12. GATA-3 and STAT-6 were also low in both CD and control mucosa. In normal duodenal biopsies, IFN- stimulated T-bet through a STAT-1 dependent mechanism. Challenge of treated CD but not control biopsies with gliadin enhanced T-bet and this effect was also inhibited by STAT-1 inhibition.

Conclusions: This study shows that activation of STAT-1 by IFN- promotes T-bet in CD mucosa.

Abbreviations: CD, coeliac disease; Th1, T helper cell type 1; Th2, T helper cell type 2; IFN, interferon; IL, interleukin; T-LPL, lamina propria T lymphocytes; EMA, antiendomysial antibodies; DMSO, dimethylsulphoxide; PT, peptic-tryptic digest of gliadin; LPMC, lamina propria mononuclear cells

Keywords: coeliac disease; T-bet; STAT-1

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